Technical Field
The present invention relates to the field of medicinal chemistry, and in particular, to a 2-aryl selenazole compound and application thereof. The present invention further relates to a method for preparing the compound, a pharmaceutical composition including the compound, and medical uses thereof, especially application as a xanthine oxidase inhibitor in treatment of gout and hyperuricemia.
Related Art
Gout is a disease caused by deposition of sodium urate in vivo when an excessively great amount of uric acid is generated due to disorder of purine metabolism in vivo. Gout is a second largest metabolism disease following diabetes, and has been listed by UN as one of the twenty most chronic and stubborn diseases in 21st century. According to epidemiological studies at home and abroad, with improvement of living level and increase of average lifetime of human beings, the incidence of hyperuricemia and gout shows an increasing tendency. It was reported that, during ten years from 1990 to 1999, the incidence of gouty arthritis in U.S. was increased from 0.29% to 0.52% (Arthur L. Weaver. Epidemiology of gout [J]. Cleveland Clinic Journal of Medicine 2008, 75 (Suppl 5): S9-S12); in a national health investigation carried out between 2007 and 2008, 8.3 million Americans reported that they were informed by their doctors that they suffered from gout; and the incidence thereof in UK and German was 1.4% during a period from 2000 to 2005 (L. Annemans, E Spaepen, M Gaskin, et al. Gout in the UK and Germany: prevalence, comorbidities, and management in general practice 2000-2005 [J]. Ann Rheum Dis, 2008, 67: 960-966). From an epidemiological study for 3978 urban persons aged 40 to 74, which was carried out in China in 2010, it was shown that 25% of investigated persons suffered from hyperuricemia (Raquel Villegas, Yong bing Xiang, Qiu yin Cai, et al. Prevalence and Determinants of Hyperuricemia in Middle-Aged, Urban Chinese Men [J]. Metabolic Syndrome and Related Disorders, 2010, 8(3):263-270); and the incidence thereof in inland regions was lower than that in coastal regions, while the incidence thereof in undeveloped areas was lower than that in developed areas (Hairong Nan, Qing Qiao, Yanhu Dong, et al. The prevalence of hyperuricemia in a population of the coastal city of Qingdao, China [J]. The Journal of Rheumatology, 2006, 33(7):1346-1350.). According to an analysis report from the Chinese Center for Diseases and Health Investigation in 2004, the number of hyperuricemia patients had then reached 0.12 billion in China, including more than 75 million gout patients, and in addition, the number was increasing at an annual growth rate of 0.97%, which seriously endangers people's life and health.
The occurrence of gout is caused by hyperuricemia due to constant increase of uric acid level in vivo. With supersaturation of uric acid level, sodium urate is crystallized and deposited in such sites as joints and soft tissues. When the uric acid level in vivo changes rapidly, and a partial wound leads to release of microcrystals or change of urate crystal protein coating, an inflammatory reaction of gout is caused, and then gout is induced. Uric acid is an end product of purine metabolism in nucleic acid (including nucleic acid in foods) in vivo. The content thereof is related with catabolism rate of nucleic acid in vivo and renal excretory function. When the generation of uric acid increases or excretion of uric acid reduces, it may both lead to deposition of uric acid and occurrence of hyperuricemia. It is generally believed that hyperuricemia occurs when the content of uric acid in serum is >420 μmol/L (70 mg/L) for male and >360 μmol/L (60 mg/L) for female at 37° C.
Gout may also cause many complications. According to statistics, for 90% gout patients, impotence, nephritis, calculus and the like will be induced, and complications such as chronic nephrosis and heart diseases may also be caused; for 50% patients, serious deformation of joints easily occurs and then causes disability; and for 30% patients, diseases such as uremia and renal failure are easily induced and then cause death (Grobner W, Walter-Sack I. Treatment of hyperuricemia and gout [J]. Med Monatsschr Pharm. 2005, 28(5): 159-164). Gout is also related with multiple diseases such as hypertension, metabolic syndrome, hyperlipidaemia, diabetes and insulin resistance (Terkeltaub R A. Clinical practice. Gout [J]. N Engl J Med. 2003, 349: 1647-1655) (Schlesinger N, Schumacher H R Jr. Gout: can management be improved ? [J]. Curr Opin Rheumatol. 2001, 13: 240-244).
Currently, medicines used for gout treatment mainly include anti-inflammatory agents, uricosuric drugs and uric acid production inhibitors.
Some anti-inflammatory agents such as colchicines, non-steroidal anti-inflammatory drugs (NSAIDS), adrenocorticotrophic hormone (ACTH), and glucocorticoid are mainly used for treatment of acute gouty arthritis, which can relieve patients from temporary pains. Colchicines is often accompanied by common adverse reactions such as diarrhea, emesis, and a spasm of abdominal pain; and non-steroidal anti-inflammatory drugs can relieve pains within a short period, but most of the non-steroidal anti-inflammatory drugs are accompanied by a serious gastrointestinal reaction. Adrenocorticotrophic hormone and glucocorticoid can inhibit infective inflammation, reduce hyperemia and edema, inhibit movement of inflammatory cells, and reduce individual immune level, which are used for treatment of severe acute gout patients accompanied with constitutional symptoms. However, such drugs have a strong rebound effect.
The uric acid level in vivo shall be reduced radically so as to better cure gout. The uric acid level in vivo is reduced mainly by two means of promoting uric acid excretion and reducing uric acid generation. Currently, drugs for promoting uric acid excretion in vivo mainly include probenecid, anturan, benzbromarone and the like. These drugs can inhibit reabsorption of uric acid by kidney tubules, and act on urate transporters of renal proximal tubules, thereby inhibiting reabsorption of uric acid, increasing excretion thereof, and consequently reducing the concentration of uric acid in vivo. Probenecid is developed by Merck Corp. (U.S.), with main side-effects of erythra, severe gastrointestinal stimulation, drug fever and the like. Benzbromarone (Narcaricin) developed by Sanofi-Synthelabo Ltd (France) and marketed since 1976, and anturan developed by Navatris Corp. (U.S.) and marketed since 1959, have the same action principle as probenecid. It was found through researches that due to main side-effects of such drugs, urine shall be alkalized when the drugs are administered to patients, and the drugs cannot be applied in patients with renal insufficiency. In addition, it was reported according to researches that benzbromarone has a very great hepatotoxicity, and so has been withdrawn from most of the European market (Jansen T L, Reinders M K, van Roon E N, et al. Benzbromarone with drawn from the European market: another case of “absence of evidence is evidence of absence”? [J]. Clin Exp Rheumatol, 2004, 22 (5):651).
Another type of drugs used for gout treatment are uric acid production inhibitors. Researches indicated that such drugs mainly inhibits transformation of purine to uric acid through inhibiting the activity of xanthine oxidase (XO) required in the procedure of purine metabolism, so as to radically reduce generation of uric acid, thereby taking effect of gout treatment. Allopurinol marketed in 1960s, as an analogue of hypoxanthine, is a competitive inhibitor of xanthine oxidase. Allopurinol is mainly applied in patients with renal insufficiency. Although allopurinol has been applied for half a century, patients are often accompanied with fever, allergic eruption, abdominal pain, diarrhea, and reduction of leukocytes and platelets, and it even has side-effects such as hepatic function damage. It was found through researches that oxipurinol, a metabolite of allopurinol, can also inhibit the activity of xanthine oxidase, but it was also found that toxic and side effects of allopurinol are also resulted from a metabolite thereof such as oxipurinol.
Febuxostat is a new generation of xanthine oxidase inhibitor, which is applied clinically in prevention and treatment of hyperuricemia and induced gout. Teijin (Japan) applied for marketing of febuxostat at the beginning of 2004, EU approved marketing thereof in May, 2008 and FDA (U.S.) approved marketing thereof in February 2009. Febuxostat can inhibit oxidation and reduction states of xanthine oxidase. By comparison, allopurinol has a weak capability of inhibiting oxidation state of xanthine oxidase. Febuxostat is metabolized mainly though hepar, while allopurinol is metabolized and excreted mainly through kidney, which can better avoid adverse effects of allopurinol caused by renal metabolism and excretion (Takano Y, Hase-Aoki K, Horiuchi H et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase [J]. Life Sci. 2005, 76: 1835-1847) (Becker M A, schumacher H R Jr, Wortman R L. Febuxostat compared with allopurinol in patients with hyper-uricemia and gout [J]. N Engl J Med. 2005, 353: 2450-2461). According to a Phase III clinical test report, compared with a control group, the uric acid level of plasma in a treatment group is lower than 60 mg/L after completion of treatment. Patients sensitive to allopurinol can better adapt to febuxostat. Compared with a dosage of 300 mg/d allopurinol, a dosage of 80 mg/d to 120 mg/d febuxostat can more effectively reduce the urate level of plasma (Pohar S, Murphy G. Febuxostat for prevention of gout attacks [J]. Issues Emerg Health Technol. 2006, 87:1-4).
Xanthine oxidase inhibitors with a target spot of xanthine oxidase are all almost heterocyclic compounds till now, and are mostly nitrogen heterocyclic aromatic compounds, for example, phenyl pyrazole derivatives (WO9818765, JP10310578), 2-phenyl thiazole derivatives (WO9631211, JP2002105067), 3-phenyl isothiazole derivatives (JP6211815), C-fused pyridine derivatives (WO2005121153), 2-phenyl thiophene derivatives (WO2006022375), 2-phenyl pyridine derivatives (WO2006022374), aryltriazole compounds (Nakazawa T, Miyata K, Omura K, et al. Metabolic profile of FYX-051 (4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the rat, dog, monkey, and human: identification of N-glucuronides and N-glucosides [J]. Drug Metab Dispos, 2006, 34(11): 1880-1886), triaryl formic acid derivatives (WO2007043457), and the like as reported. Because such drugs can radically reduce generation of uric acid and take effect of gout treatment, great importance is attached to development of the drugs. With further research on a target spot of xanthine oxidase, and constant development of computers and the like, crystal structure of xanthine oxidase is completely analyzed, so as to further identify function mechanism of the drugs, thereby establishing a necessary basis for research on these drugs.
In last decades, the development of xanthine oxidase inhibitors was slow, which is related with a small proportion of hyperuricemia and gout patients. However, the incidence of hyperuricemia and gout showed an increasing tendency in recent years, which attracted great attention of researchers on anti-gout drug studies. Meanwhile, with further research on xanthine oxidase and reductase, it was found that inhibition of the activity of xanthine oxidase and reductase can contribute to treatment of hyperuricemia, and has a certain treatment effect of ischemia/ischemia-reperfusion injury and especially heart failure, which indicates that a xanthine oxidase inhibitor with high efficiency and low toxicity has huge development potentials and application values. With respect to the chronic and stubborn disease of gout, design of new drugs with an action target of xanthine oxidase has attracted great attention widely. Multiple compounds with high activity have gone through clinical tests. However, there are many problems faced such as great toxic and side effects, which need to be researched more deeply.